The invention relates to the use of glucocorticoid receptor antagonists for the prevention and treatment of diseases of the male reproductive system, as well as to glucocorticoid receptor antagonists, which are particularly suitable for this purpose.
It is well known that physical and/or mental stress, age as well as exogenous factors, such as drugs and excessive consumption of alcohol, can lead to sexual dysfunctions and hypogonadism in men. According to presently existing understanding, these diseases are caused by a decreased androgen production, especially by a decreased testosterone production.
Various attempts were made to treat the above diseases. However, the drugs used either were not sufficiently effective or showed serious side effects, which harmed the patients more than they healed them or were not suitable for other reasons.
There is therefore an appreciable demand for new compounds to prevent and/or treat the diseases above.
It is therefore an object of the present invention to be able to prevent and treat the symptoms, caused by a decreased androgen production. It is furthermore an object of the present invention to make available compounds, which can be used advantageously for the treatment and/or prevention of diseases, which are caused by a decreased androgen production.
Pursuant to the invention, the aforementioned objective is accomplished by the use of glucocorticoid receptor antagonists. Within the meaning of the present invention, glucocorticoid receptor antagonists are understood to be drugs, which inhibit the action of glucocorticoids by binding to glucocorticoid receptors.
The present invention is based on the surprising realization that, when glucocorticoid receptor antagonists are administered, the androgen production, which previously was decreased by the excess of glucocorticoid, is increased.
If for example Leydig cells (cells from the testes, which produce male sex hormones) are stimulated with human chorion gonadotropin (hCG), there is an increase in testosterone production due to these cells. If now the cells are incubated with hCG and a glucocorticoid, such as dexamethasone (a ligand for the glucocorticoid receptor (GR)), a significant decrease in testosterone production can be observed. It has now been found that the decrease in testosterone production is prevented by the glucocorticoid, if the latter is administered together with a glucocorticoid receptor antagonists in such an experiment. This effect was observed not only in cells, but also in experimental animals.
In experimental animals, stress or an increased glucocorticoid blood level cause an inhibition of the secretory activity of the endocrine system of the male gonads, which is documented by a decreased serum testosterone level. At the same time, an inhibition of (decrease in) male sexual activity is observed. These symptoms are characteristic, for instance, of hypogonadism and are observed in other syndromes, such as stress and, in particular, chronic stress.
Glucocorticoid receptor antagonists, which may be natural or synthetic compounds, occupy the glucocorticoid receptor and, in doing so, displace the natural (endogenous) ligand of the glucocorticoid receptor, the glucocorticoids, so that, by a selective antagonization of the glucocorticoid receptor, the transfer of chemical signals over this receptor, at the very least, is reduced, but may even also be prevented almost completely. By the displacement of the glucocorticoids by glucocorticoid receptor antagonists, the excessive occupation of glucocorticoid receptors by glucocorticoids is antagonized.
This reduction in or prevention of the occupation of the glucocorticoid receptors by glucocorticoids may be desirable especially if the glucocorticoid level in the body is increased. Such an increase can be caused, for example, by (i) physical or mental stress, (ii) a pathological increase in the secretory activity of the adrenal cortex, (iii) alcohol and drug misuse and withdrawal, (iv) exogenous administration of medicinal drugs, such as cortisol, for the treatment of chronic diseases and (v) aging.
If the realizations and experimental results, described above, are combined, they lead to the assumption, without being definitive, that the excessive secretion of glucocorticoids results in an excessive occupation of glucocorticoid receptors in endocrine cells of the male gonad and/or in the relevant regions of the central nervous system. This can cause disorders of the male reproductive system due to a decrease in the production of male sex hormones (androgens, especially testosterone), an impairment of the responsiveness of the endocrine system of the male gonads for the stimulating effect of gonadotropin, an impairment of the neuronal responsiveness to sexual stimuli and, consequently, an erectile dysfunction. These symptoms are described generally by the expression xe2x80x9chypogonadism in malesxe2x80x9d, which includes a plurality of somatic and endocrine dysfunctions. In the sense of the present invention, xe2x80x9chypogonadismxe2x80x9d does not include the consequences of the surgical removal (gonadectomy) or of the congenital defects (agenesia) of the male gonads.
Especially the hypogonadism in males, especially the hypogonadotropic hypogonadism, sexual dysfunctions in males and infertility can be treated and/or prevented particularly well by administering glucocorticoid receptor antagonists, the excessive occupation of the glucocorticoid receptors by glucocorticoid receptor antagonists in the organism, especially in the organs responsible for reproduction and/or in neuronal circuits, which are responsible for its control, being reduced or prevented.
There are two mechanisms, by means of which the interaction between glucocorticoids and glucocorticoid receptors can proceed. The type 1 mechanism is distinguished by an interaction between the glucocorticoid receptor and special DNA sequences. On the other hand, the interaction between glucocorticoid receptors and other transcription factors, in the absence of specific DNA binding, participates possibly over a direct proteinxe2x80x94protein intraction in the type 2 mechanism.
In a preferred embodiment, the glucocorticoid receptor antagonist, which is used pursuant to the invention, antagonizes the type I transcription induction of the glucocorticoid receptor gene. A particularly good therapeutic effect is noted in the treatment of the aforementioned diseases when glucocorticoid receptor antagonists are used. It is well known that glucocorticoid play an important role in the immune system. Since the glucocorticoid-induced immune suppression takes place exclusively by the type 2 mechanism of the glucocorticoid receptor action, glucocorticoid receptor antagonists are preferred, which antagonize the type 1 transcription induction of the glucocorticoid receptor gene, since by these means no negative effects on the immune system can be detected.
In a preferred embodiment, the glucocorticoid receptor essentially does not antagonize the type 2 transcription inhibition. When glucocorticoid receptor antagonists with this property were used pursuant to the invention, it was not possible to detect any side effects, especially side effects on the immune system. In this connection, the expression xe2x80x9cessentially does not antagonizexe2x80x9d means that possible antagonizing can be detected only insofar as non-physiological or pathological effects were not observed.
Preferably, the glucocorticoid receptor antagonist employed for the inventive use, essentially do not bind to other steroid receptors. In this connection, the expression xe2x80x9cessentially do not bindxe2x80x9d means that only sufficient glucocorticoid receptor antagonist binds to other steroid receptors as glucocorticoid receptors, so that no effects, brought about by the other receptors, can be noted or existing physiological effects are eliminated. Examples of other steroid receptors are the mineral corticoid receptors, estrogen, progesterone receptors and androgen receptors. Due to this high selectivity of the glucocorticoid receptor antagonists, which are used pursuant to the invention, the effects desired pursuant to the invention, are particularly clearly pronounced and, with that, the diseases which are to be treated pursuant to the invention, can be treated particularly well. On the other hand, undesirable side effects, especially those caused by an occupation of other glucocorticoid receptors, are not observed.
Preferably, the signals, transferred by glucocorticoid receptors are not inhibited completely by the glucocorticoid receptor antagonists, which are used pursuant to the invention. In this connection, it should be pointed out that, for maintaining basic vital functions and for an adequate adaptation to challenges brought about by the environment, a certain level of signals, transmitted by glucocorticoid receptors, is necessary. For these reasons, a complete inhibition of signals, transferred by glucocorticoid receptors, is not desirable, especially in order to prevent undesirable effects of the interruption of the feedback, brought about by glucocorticoids (that is, iatrogenic glucocorticoid receptor resistance) and an uncontrolled pituitary-adrenal hyperactivity.
For the inventive use, the glucocorticoid receptor antagonists can be administered enterally and parenterally, for man especially in a dose of 0.0001 to 100 mg per kg of body weight. The glucocorticoid receptor antagonist can be administered together with pharmaceutically suitable adjuvants. The glucocorticoid receptor antagonists can be pressed into a solid-dose unit, such as a tablet or be present in some way, such as capsules or suppositories. By using pharmaceutically compatible liquids, the glucocorticoid receptor antagonists can also be prepared in the form of solutions, suspensions, emulsions, as injection preparations, droplets or sprays. Medicinal drugs for the inventive use furthermore may contain additives, such as fillers, dyes and polymeric binders. Basically, any pharmaceutically compatible additive can be used, which does not interfere negatively with the function of the glucocorticoid receptor used pursuant to the invention. Suitable carriers, with which the glucocorticoid receptor antagonists can be administered, comprise lactose, starch cellulose derivatives and mixtures thereof.
Glucocorticoid receptor antagonists may be compounds, which are known. In the case of unknown compounds, it is possible to carry out simple tests, which are known to those skilled in the art, to establish whether these compounds have the properties of a glucocorticoid receptor antagonist. For this purpose, for example, a compound, which is to be tested, is incubated together with a glucocorticoid in a test system for glucocorticoid receptors and tested to establish whether the effect, brought about by the glucocorticoids, is reduced in the presence of the antagonist in this test system.
Glucocorticoid receptor antagonists are, for example the 11,21-bisphenyl-19-norpregnane derivatives, which are described, for example, in the EP 683 172 A1 and have the formula 
in which R1represents hydrogen, halogen, (1-6C) alkoxy and NR5R6, R5 and R6 being selected independently of one another from hydrogen, and (1-6C) alkyl or R5 and R6 together forming a (3-6C) alkylene, R2 represents hydrogen, or R1 and R2 together form a (1-3C) alkylenedioxy group, which optionally is substituted with one or more halogen atoms, R3 represents methyl or ethyl, R4 is selected from C(O)xe2x80x94NR5R6, SOn-(1-6C) alkyl, which optionally is substituted by one or more halogen atoms, or SOn-(3-6C) cycloalkyl, n being 1 or 2, SO2-NR5R6,2-oxypyrrolidinyl and NR5R6, R7 represents hydrogen or (1-6C) alkyl, R8 represents hydrogen or a carboxy-1-oxo(1-6C) alkyl and X is selected from (H, OH), O, and NOH. These are particularly suitable for the inventive use, because the appropriate diseases can be treated particularly well.
Other glucocorticoid receptor antagonists, also suitable for the inventive use because the aforementioned diseases can be treated well, are the 11-(phenyl substituted)-estra-4,9-diene derivatives described in the EP 0 763 541 A1 and having the formula 
in which A represents a 5- or 6-membered ring with two hetero atoms, which are not linked to one another and are selected independently from O and S, the ring optionally being substituted by one or more halogen atoms, or A represents a 5- or 6-membered ring, which does not have any carbon-to-carbon double bonds and contains one hetero atom, which is selected from O and S, the hetero atom being linked to a phenyl group at the position marked with a star, the ring optionally being substituted by one or more hydrogen atoms, R1 representing hydrogen or 1-oxo(1-4C) alkyl, R2 representing hydrogen, (1-8C) alkyl, halogen or CF3, X being selected from (H, OH,) O and NOH and the dashed line representing an optionally present bond.
Other glucocorticoid receptor antagonists, like those described in WO 01/44267, can be found among compounds represented by the following formula 
in which R1 represents a C1-6 alkyl group, R2 is a hydrogen atom, a C1-6 alkyl group or a C1-6 acyl group, X is a hydroxyl group or a trimethylsiloxy group and Y is a hydrogen atom or a perfluoroalkyl group of the general formula CnF2n+1, or X and Y together represent an oxo group or an oximino group NOR3, Z represents a hydrogen atom, a C1-6 alkyl group or a substituted methylene group CH2W, in which W represents a hydroxyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a halogen atom or pseudohalogen, and A represents an oxo group, an oximino group NOR3, a 1,3-dithian group or a 1,3-dithiolan group, R3 being a hydrogen atom, a C1-8 alkyl, aryl, alkylaryl or arylalkyl group, or a C1-8 acyl group, a CONHR4, COSR4 or COOR4 group, R4 being a hydrogen atom or a C1-8 alkyl, aryl, alkylaryl or arylalkyl group and n a whole number from 1 to 4.
As glucocorticoid receptor antagonists, the compounds RU38486 (EP 0057 115) and KB 285 (WO 99/63976) of the two following structural formulas also come into consideration: 
As glucocorticoid receptor antagonists, the compounds, which are given in the following formula and are also an object of the present invention, are particularly suitable because of their especially good effect when used for the treatment of the diseases named above: 
wherein R6 is a hydrogen atom or a halogen atom, such as fluorine, chlorine or bromine, in the xcex1 or xcex2 position, or a C1-6 alkyl group in the xcex1 or xcex2 position,
R7, independently of R6, is a hydrogen atom or a halogen atom, such as fluorine, chlorine or bromine, in the xcex1 or xcex2 position, or a C1-6 alkyl group in the xcex1 or xcex2 position,
R11 is a hydrogen atom, a C1-6 alkyl group, a C1-6 acyl group, a CONHR21, COSR22, or COOR22 group, R21 being a C1-6 alkyl group or a substituted or not substituted C6-C10 aryl group and R22 a C1-6 alkyl group or a substituted or not substituted C6-10 aryl group,
R13 is a methyl or ethyl group,
R17 is a hydrogen atom or a C1-6 alkyl group C1-6 acyl group and
R20 is a hydrogen atom, a C16 alkyl group or a substituted or not substituted C6-12 aryl group.
Examples of aryl groups are phenyl to naphthyl groups. These may have one or more substituents, which are selected independently of one another. The substituents may be in the o-, m- or p-position. Examples of substituents are linear or branched C1-C6 alkyl groups, such as methyl, ethyl, propyl or isopropyl, halogens, such as chlorine or bromine, and pseudohalogens, such as azide or rhodonide groups. The substituents of the aryl groups, particularly in the case of R20, furthermore may be substituted phenyl groups, selected from sulfonamides of the type C6H4SO2NR21R22, sulfonalkyls of the type C6H4SO2R23, aminosulfones of the type C6H4NHSO2R23 or hydroxysulfonealkyls of the type C6H4OSO2R24 in which R21 to R24 are linear or branched C1-C6 alkyls, such as methyl, ethyl, propyl or isopropyl.
Because of their particularly positive properties in treating the aforementioned diseases, preferred representatives of the inventive compounds are:
4-(17xcex1-ethinyl-17xcex2-hydroxy-3-oxoestra-4,9-diene-11xcex2-yl)benzaldehyde-1(E)-oxime,
4-(17xcex1-ethinyl-17xcex2-methoxy-3-oxoestra-4,9-diene-11xcex2-yl)benzaldehyde-1(E)-oxime,
4-(17xcex2-hydroxy-17xcex1-propinyl-3-oxoestra-4,9-diene-11xcex2-yl)benzaldehyde-1(E)-oxime,
4-(17xcex2-methoxy-17xcex1-propinyl-3-oxoestra-4,9-diene-11xcex2-yl)benzaldehyde-1(E)-oxime,
4-[17xcex2-hydroxy-17xcex1,21-(phenyl)19nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-hydroxy-17xcex1,21-(4xe2x80x2-methylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-hydroxy-17xcex1,21-(t-butyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-hydroxy-17xcex1,21-(4xe2x80x2-t-butylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-hydroxy-17xcex1,21-(4xe2x80x2-methylsulfonylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-hydroxy-17xcex1,21-(4xe2x80x2-methylsulfonylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-[N-(ethylamine)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1,21-(4xe2x80x2-methylsulfonylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-[S-(ethylthio)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1,21-(4xe2x80x2-methylsulfonylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-[O-(ethyloxy)carbonyl]oxime,
4-[17xcex2-hydroxy-17xcex1-propinyl-13xcex2-ethyl-3-oxoestra-4,9-diene-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[6xcex2-chloro-17xcex2-hydroxy-17xcex1-propinyl-3-oxoestra-4,9-diene-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[7xcex1-methyl-17xcex2-hydroxy-17xcex1-propinyl-3-oxoestra-4,9-diene-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-acetoxy-17xcex1-propinyl-3-oxoestra-4,9-diene-11xcex2-yl]-benzaldehyde-1(E)-oxime,
4-[17xcex2-acetoxy-17xcex1,21-(4xe2x80x2-methylsulfonylphenyl)19-nor-3-oxopregna-4,9-diene-20-yn-11xcex2-yl]-benzaldehyde-1(E)-O-acetyloxime,
4-[17xcex2-hydroxy-17xcex1-propinyl-3-oxoestra-4,9-diene-11xcex2-yl]-benzaldehyde-1(E)-[N-trifluoromethoxy-phenylamino)carbonyl]oxime.
The above compounds are particularly suitable for treating and/or preventing diseases, brought about by an androgen deficiency.
The present invention furthermore relates to a method for the synthesis of the inventive compounds, for which 11xcex2-formylphenylsteroids of the general formula 
are reacted with hydroxylamine, salts of hydroxylamine, such hydroxylamine hydrochloride or hydroxylamine hydrogen sulfate, in solvents, such as pyridine, dimethylformamide or alcohols, in the presence of bases, such as alkali or alkaline earth carbonates or hydroxides, or potassium t-butanolate, to the corresponding 11 xcex2-benzaldoximes of the aforementioned formula and the hydroxyl groups optionally are etherified, esterified or converted into urethane groups.
With this inventive method, it is possible, in a particularly simple, fast and inexpensive manner, to synthesize the inventive compounds in a highly pure form and in high yields.